—  SPECIALTY CONFERENCE  —

Head/Neck/Endocrine Pathology

Case 4 - Acinic Cell Adenocarcinoma with High-Grade Transformation

Bruce Wenig
Beth Israel Medical Center
New York, NY





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Clinical History
69 year old women with a left parotid gland mass measuring 3 cm in greatest dimension. The tumor was rapidly growing with associated facial nerve weakness. An enlarged left cervical neck (Level II) was also present. A radical parotidectomy and neck dissection was performed.


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Diagnosis:
Acinic cell adenocarcinoma with high-grade transformation ("dedifferentiated" acinic cell adenocarcinoma).

Acinic Cell Adenocarcinoma (ACC)

Definition
Malignant epithelial salivary gland neoplasm characterized by a variety of histologic growth patterns and the tendency for at least some of the neoplastic cells to recapitulate the appearance of normal serous acinous cells characterized by the presence of cytoplasmic (zymogen type) secretory granules. Synonyms have included acinous or acinic cell tumor considered an inappropriate designation given the malignant biologic potential of this neoplasm.

Clinical Features
ACC represents approximately 18% of all malignant salivary gland neoplasms and 6.5% of all salivary gland neoplasms. ACC is slightly more common in women than in men; occurs over a wide age range with a peak incidence in the 7th decade of life:
  • approximately 4% occur in children;

  • in children, the majority of cases occur in the second decade of life;

  • in children, acinic cell adenocarcinoma is the second most common malignant epithelial neoplasm second to mucoepidermoid carcinoma;
The majority of cases (>80%) arise in the parotid gland. Uncommonly, ACC may also be identified in the submandibular and sublingual glands, as well as in all minor salivary glands, especially those of intraoral sites; the most common intraoral sites include the buccal mucosa and upper lip. Bilateral parotid gland, and less often bilateral submandibular gland involvement, may uncommonly occur. The most common clinical presentation is that of a slow-growing, solitary mass without fixation to surrounding structures. Associated pain may or may not be present. Facial paralysis may occur in up to 10% of patients and fixation to surrounding structures may uncommonly occur. The duration of symptoms typically are less than a year but may occur up from several years to decades.

Etiology
There are no known etiologic factors.

Pathology

Fine Needle Aspiration Biopsy
Aspirates of ACC tend to be cellular except for the papillary-cystic and follicular variants, which may have low numbers of serous acinar cells. The cytologic diagnosis of ACC rests on the presence of identifying serous acinar cells characterized by the presence of:
  • large cells with round, relatively uniform dark staining nuclei, inconspicuous to conspicuous nucleoli and abundant, granular appearing cytoplasm;

  • appear in clusters resembling normal acini or as individual cells;

  • stripped or naked nuclei may be present in the background, and may be mistaken for lymphocytes;

  • in contrast to normal (nonneoplastic) serous acinar cells in which the cells have basally oriented nuclei, the nuclei in neoplastic acinar cells tend to be centrally situated lacking polarity;

  • the histology of acinar cell adenocarcinoma often includes the presence of a lymphocytic cell infiltrate, which may be apparent in aspirates of this tumor.
Serous acinar cells may be mistaken for oncocytic cells and in conjunction with a lymphocytic cell infiltrate may be misdiagnosed as a Warthin tumor.

Gross
ACCs are well-demarcated and/or encapsulated, round or multilobulated, soft to rubbery, tan-gray to yellow or pink mass usually measuring from 1-3 cm in greatest diameter but occasionally may reach sizes up to 13 cm. Most neoplasms have a homogenous appearance but may be cystic and hemorrhagic. Recurrent neoplasms are less well-demarcated and tend to be multinodular in appearance.

Histology
ACCs often are circumscribed tumors and may be encapsulated or may be infiltrative. ACCs are polymorphic tumors characterized by a variety of growth patterns including solid, microcystic, papillary-cystic and follicular.

Growth Patters:

1) Solid and microcystic :
  • most common patterns and often seen in association with each other;

  • solid growth consists of sheets or aggregates of tumor cells in lobules or organoid arrangement;

  • microcystic consists of numerous small cystic spaces; microcysts may appear as empty spaces or may contain eosinophilic to basophilic material.

2) Papillary-cystic:
  • less common patterns than solid and microcystic but more common than follicular pattern;

  • papillary-cystic consists of variable-sized cystic spaces associated with papillary projections supported by a thin fibrovascular core:
    • epithelial proliferation may appear to be "floating" in cystic spaces;

    • epithelial cells may bulge into the lumen in an uneven manner resulting in a "tombstone row" appearance.

3) Follicular pattern :
  • follicular pattern resembles thyroid parenchyma with epithelial-lined lumens containing eosinophilic proteinaceous material lined by cuboidal to columnar cells.

Cytomorphology
ACCs are also noteworthy for their cytologic variation including:

1) Acinic or acinar cells : these cells are diagnostic (pathognomonic) appear polyhedral in shape with small dark eccentrically placed nuclei and characteristic abundant basophilic cytoplasm with cytoplasmic (zymogen-like secretory) granules; the zymogen-like secretory granules define these as acinar cells. These cells may predominate in well-differentiated tumors, but in any given tumor they may represent a minority of the neoplastic cells; in the latter situation, histochemical stains are helpful in the diagnosis (see below). These cells may be vacuolated and in contrast to vacuolated (non-acinar) cells retain their cytoplasmic diastase-resistant, PAS-positivity.

2) Intercalated duct-like cells : these cells are cuboidal or columnar with centrally placed small dark nuclei and eosinophilic to amphophilic cytoplasm. They are found in the majority of tumors but usually represent a smaller percentage of the cellular components; may predominate in about 1/3 of cases.

3) Vacuolated cells : contain clear cytoplasmic vacuoles which may be numerous, vary in size and distend the cell membranes. These cells are more commonly seen in ACC than in other salivary gland neoplasms, but they are not in and of themselves diagnostic for acinic cell adenocarcinoma.

4) Clear cells : appear round to oval cells with distinct cell borders, peripherally-placed, small, dark nuclei and the hallmark clear cytoplasm; result from fixation and/or tissue processing. These cells are considered an uncommon cell type in acinar cell adenocarcinomas. Likely "pure" clear cell variant of acinic cell adenocarcinoma doesn't exist.

5) Nonspecific glandular cells : lack specific features seen in the other cell types and appear round to polygonal with round nuclei, amphophilic to eosinophilic cytoplasm and indistinct or ill-defined cell borders; tend to be more cellular and pleomorphic with a syncytial growth.

Additional Features
While a single growth pattern and cell type may predominate in any given tumor, it is not uncommon to see multiple growth patterns and cell types in a single tumor. In the majority of ACCs, there is minimal cellular pleomorphism and low to absent mitotic activity. Typically, the stroma is scant but occasionally may be dense and hyalinized. A prominent lymphoid component with germinal centers is present in many ACCs and has been referred to as Tumor-Associated Lymphoid Proliferation (TALP). The presence of TALP, including germinal centers may suggest involvement of a periparotid or intraparotid lymph node; the presence or absence of subcapsular sinuses assist in differentiating TALP from a bona fide lymph node. TALP is not unique to ACC and can be seen in a variety of salivary gland neoplasms. Occasionally, psammomatoid concretions similar to those seen in thyroid papillary carcinoma may be present. Hemorrhage may be present including in connective tissue and within epithelial cells; intracytoplasmic hemosiderin pigment appears finely granular. Of note that invasive growth is not a prerequisite for a diagnosis of ACC and the diagnosis can (and should) be even in the absence of invasive growth on the basis of the architectural and cytomorphologic features. As far as is currently known, there is no benign counterpart for ACC.

Special Stains

Histochemistry
Acinar cells and intercalated duct cells show the presence of intracytoplasmic diastase-resistant, PAS-positive granules; mucicarmine and alcian blue staining are typically negative but may be weakly positive in any given case. The presence of some intracytoplasmic mucicarminophilic material can be seen in ACC and does not exclude the diagnosis. All of the other cell types including vacuolated cells, clear cells and non-specific glandular cells may show diastase-sensitive, PAS-positive intracytoplasmic material, and are mucicarmine and alcian blue negative.

Relative to specific patterns, in the microcystic pattern eosinophilic to basophilic material may stain for PAS and mucicarmine; in the papillary-cystic pattern, intraluminal and extracellular PAS positive and mucicarmine positive material may be present; in the follicular pattern, luminal material may be PAS positive and weakly mucicarmine positive.

Immunohistochemistry :
Immunostaining is non-specific in the diagnosis and differential diagnosis of ACC. Cytokeratins are consistently positive. While normal acinar cells are reactive for anti-amylase, neoplastic acinar cells are usually nonreactive. Variable immunoreactivity is seen with S-100 protein and vimentin. p63, calponin and actins (smooth muscle and muscle specific) are negative. There may be a high expression of p53 and bcl-2, and a low labeling index with Ki-67 (MIB1).

Electron microscopy :
Ultrastructural findings are characterized by the presence of numerous round, electron dense cytoplasmic secretory granules; rough endoplasmic reticulum and mitochondria are present; junctional complexes and microvilli may be identified; basal lamina separates tumor cells from stroma.

Cytogenetics and Molecular Biology :
To date, there have been only a few studies on cytogenetics and molecular biology showing the presence of alterations of chromosome 4p, 5q, 6p and 17p, as well as loss of heterozygosity (LOH) in at least one of the 20 loci on chromosomes 1, 4, 5, 6, and 17.

Treatment and Prognosis
The treatment for ACC includes complete surgical excision and may consist of either conservative parotidectomy when the tumor is limited to the superficial lobe or total parotidectomy when the deep lobe of the parotid is involved. For non-parotid gland sites of involvement, conservative but complete surgical resection to include tumor-free margins is indicated. Adjunctive radiation therapy is generally not used as a primary mode of treatment but may be utilized for tumors that cannot be completely resected or in the presence of metastatic disease. ACCs are indolent neoplasms generally cured by complete surgical removal. ACCs have a 5-year disease specific survival of 91%. However, there is an approximately 35% recurrence rate, approximately 16% metastatic rate and approximately 16% disease-associated death rate. Depending on the primary site of occurrence regional lymph node metatsasis may include the pre-auricular lymph nodes (parotid tumor), submandibular and upper jugular chain lymph nodes (submandibular tumor), submental lymph nodes (lip tumor), base of skull (palate tumor), submandibular, post-auricular and level II accessory lymph nodes (intraoral tumors). Distant visceral spread include the lungs, liver, bone and brain. Most recurrences and metastases occur within 5 years of the initial therapy; however, recurrent tumor and metastatic disease may occur years after the initial treatment.

Favorable prognostic factors include: occurrence in minor salivary glands, longer duration of symptoms, and patient's under 30 years of age. Adverse prognostic factors include multiple recurrences and metastasis (regional lymph nodes, distant visceral), short duration of symptoms, submandibular tumors more aggressive than parotid tumors and patient's over 30 years of age. Histologic features (i.e., growth patterns, cell type) are not predictive of prognosis (except for dedifferentiation, see below). Despite attempts to separate acinic cell adenocarcinomas into low- and high-grade, the histologic pattern and cytologic appearance do not correlate with either a favorable or poor clinical outcome. Clinical staging is a better predictor of prognosis than histology with poorer outcome associated with large size and infiltrative growth, involvement of the deep lobe of parotid and incomplete resection.

Acinic Cell Adenocarcinoma with High-Grade Transformation or "Dedifferentiated" Acinic Cell Adenocarcinoma
Acinic cell adenocarcinoma with high-grade transformation includes those tumors showing the presence of histomorphologically "conventional" ACC associated with areas of undifferentiated carcinoma. Similar high-grade transformation may occur in other salivary gland neoplasms including pleomorphic/monomorphic adenoma (i.e., carcinoma ex pleomorphic/monomorphic adenoma) mucoepidermoid carcinoma, adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, epithelial-myoepithelial carcinoma and others.

Clinical Features
High-grade transformation in ACC is a rare phenomenon. There is no gender predilection; tends to occur in older adults. Preferentially occurs in the parotid gland but rarely may occur in other sites. While there may be a known prior (long-standing) history of ACC, most ACCs with high-grade transformation occur de novo. Patients present with a mass lesion with or without associated pain. These tumors tend to be large with most measuring over 3 to 4 cm in greatest dimension. Metastatic disease may be present at the time of presentation and may represent the primary clinical complaint. Metastatic disease may be locoregional to cervical lymph nodes or distant metastases including to the lungs, brain and abdomen.

There are no known etiologic factors in association with high-grade transformation of ACC. There has not been a correlation to prior irradiation therapy.

Pathology
The differentiated or low-grade is composed of conventional ACC. This component may be readily identifiable or may be extremely limited in extent. The high-grade component is characterized by the presence of sheets of epithelial cells lacking evidence of cellular differentiation with marked nuclear pleomorphism, increased nuclear-to-cytoplasmic ratio, increased mitotic figures including atypical mitoses, and necrosis (individual cell and confluent [comedotype] areas). The neoplasm is extensively infiltrative including invading of residual salivary gland parenchyma, neurotropism and lymph-vascular space invasion. A desmoplastic stroma may be present. The high-grade component is devoid of any evidence of acinar cell differentiation and typically lacks an associated lymphoid proliferation.

Histochemical stains may show the presence of intracytoplasmic diastase-sensitive, PAS- positive material; mucicarmine staining is negative.

Immunohistochemical stains show the lesional cells to be variably reactive for cytokeratins (AE1/AE3, CAM5.2) but negative for p63, calponin, S100 protein, actins, trypsin, amylase and lysozyme. Other stains including EGFR, CD117, androgens and Her-2/neu have not been consistently reported in the literature but are usually negative. Recently, strong beta-catenin (membranous) staining has been reported (Skalova et al). Ki-67 (MIB1) staining will show a high proliferation index. Staining for p53 and cyclin D1 are increased in the high-grade component.

Treatment and Prognosis
Given the limited number of cases reported in the literature, there are no set guidelines for the treatment of high-grade transformation of ACC; however, since these are aggressively behaving carcinomas, therapy should be equally aggressive. Treatment includes complete surgical resection, including neck dissection given the propensity of this carcinoma to metastasize to regional lymph nodes plus adjunctive radiotherapy. Chemotherapy is added in patients with distant metastasis. High-grade transformation of ACC is associated with an accelerated clinical course with early wide dissemination and high mortality rates.

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